PROJECT SUMMARY/ABSTRACT Aerobic exercise is thought to promote healthy brain aging and to attenuate cognitive decline in seniors, and may protect from neurodegenerative disorders like Alzheimer's dementia (AD). AD is characterized by a profound pathology of the hippocampus (HC) and entorhinal cortex, two brain regions that are critical for episodic memory formation. In animal models, aerobic exercise has been shown to increase the number of adult-born hippocampal neurons. In turn, newborn neurons have been shown to improve learning and memory. Studies in humans have shown that better aerobic fitness is associated with greater performance on memory tasks in both young and older adults, but this has yet to be studied in middle-aged adults. Given the increasing prevalence of AD, research has focused on preclinical stages, prior to emergence of cognitive symptoms. In this context, examining the middle-age range is crucial, because it may be the beginning of subtle cognitive or brain changes predictive of future AD. Additionally, neuroprotective interventions may be most successful the earlier they are implemented. The goal of the proposed project is to determine the neurobiological mechanisms of hippocampal-related plasticity from a cognitive neuroscience perspective by focusing on the hippocampal subfields, which are known to be negatively affected by aging, and elucidate how fitness may modulate these mechanisms across adulthood. Aim 1 of this proposal focuses on determining the effects of aging on the behavioral capacity to disambiguate overlapping stimuli during memory formation cross-sectionally throughout adulthood. The goal of Aim 2 is to elucidate how the relationship between task performance and age may be modulated by objectively assessed aerobic fitness. Aim 3 focuses on hippocampal subfield function associated with memory formation. Aim 3 will utilize high-resolution fMRI and data-driven analytic approaches uniquely suited for detecting subtle functional changes within hippocampal subfields. Training goals include gaining expertise in 1) state-of-the-art exercise physiology methods, and developing skills in 2) experimental design for behavioral and fMRI experiments, and 3) novel data-driven approaches to analysis. The central research hypotheses are that age will be positively associated with increased performance variability during the middle age range (Aim #1), that this performance variability will interact with fitness (Aim #2), and that aerobic fitness will also modulate hippocampal activation patterns underlying memory formation (Aim #3). This research project will enhance the knowledge of the effects of early aging on hippocampal plasticity and will set a foundation from which to identify individuals who may benefit from early neuroprotective interventions.